7-152136891-C-G

Variant names:

• chr7-152136891-C-G
• rs2129088189
• NM_170606.3:c.14677G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_170606.3(KMT2C):​c.14677G>C​(p.Asp4893His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KMT2C NM_170606.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.77
• Publications: 0 publications found

Genes affected

KMT2C (HGNC:13726): (lysine methyltransferase 2C) This gene is a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family and encodes a nuclear protein with an AT hook DNA-binding domain, a DHHC-type zinc finger, six PHD-type zinc fingers, a SET domain, a post-SET domain and a RING-type zinc finger. This protein is a member of the ASC-2/NCOA6 complex (ASCOM), which possesses histone methylation activity and is involved in transcriptional coactivation. [provided by RefSeq, Jul 2008]

KMT2C Gene-Disease associations (from GenCC):

• Kleefstra syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina, Broad Center for Mendelian Genomics
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170606.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2C	NM_170606.3	MANE Select	c.14677G>C	p.Asp4893His	missense	Exon 59 of 59	NP_733751.2	Q8NEZ4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2C	ENST00000262189.11	TSL:1 MANE Select	c.14677G>C	p.Asp4893His	missense	Exon 59 of 59	ENSP00000262189.6	Q8NEZ4-1
	KMT2C	ENST00000360104.8	TSL:1	c.*1893G>C		3_prime_UTR	Exon 31 of 31	ENSP00000353218.4	H7BY37
	KMT2C	ENST00000473186.5	TSL:1	n.12547G>C		non_coding_transcript_exon	Exon 46 of 46

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.65	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.8
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.48		Loss of solvent accessibility (P = 0.0509)
MVP		0.94
MPC		2.5
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.81
gMVP		0.75
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2129088189; hg19: chr7-151833976;